As noted earlier, locus 1 (representing rs16969968) is a highly replicated association finding and furthermore rs16969968 has been shown to have functional effects on the resulting alpha5-containing receptor [19]. Therefore an important question is whether the remaining loci demonstrate additional independent effects on disease risk. Although loci 2, 3 and 4 are not highly correlated with rs16969968, |D'| is high. A high |D'| can correspond to a low r2 if the alleles that tend to co-occur on the same haplotype have very different allele frequencies. Previous results in the COGEND data suggest that there may be independent or synergistic effects on nicotine dependence between locus 1 and locus 3 [4], and haplotype analyses in the Utah and LHS samples [7], and in the COGEND and CPS-II-CPD samples [22], also indicate effects of haplotypes containing loci 1, 2 and 3.
